The invention relates to the diagnosis and treatment of conditions associated with serotonin-mediated cellular responses.
The biogenic amine serotonin plays a role in the modulation of neuronal synaptic events as well as non-neuronal cellular signaling. Serotonin acts by binding to receptors on a variety of cells. These receptors fall into two broad functional and structural categories, those acting through G-proteins to mediate intracellular signaling, and those that form ion channels. It is generally believed that serotonin may act by binding to either G-protein-coupled seven-pass transmembrane receptors, or serotonin-gated cation channels. There are six major classes of G-protein-coupled receptors, each with numerous subtypes. Thus far, there is only one class of serotonin-gated ion channels, the 5-HT3 receptor. G-protein-coupled responses can be either excitatory or inhibitory upon activation by serotonin. Activation of G-protein-coupled receptors by serotonin generally mediates responses which are slower-acting and longer-lasting, while ion channels mediate fast-acting and transitory responses. The 5-HT3 receptor, comprised of the conducting subunit, 5-HT3a and a regulatory subunit, 5-HT3b, appears to exclusively elicit excitatory responses that are generally fast-acting and transitory.
The 5-HT3 receptor is selectively permeable to cations only, such as Na+ or K+, and is very slightly permeable to Ca2+. The influx of cations, such as Na+ into a cell results in depolarization and excitatory neurotransmission. Efflux of cations, such as K+ hyperpolarizes the cell, thereby reducing the likelihood of excitation, and generally leads to inhibitory neurotransmission. Since the resting membrane of a typical cell/neuron is much less permeable to Na+ influx than to K+ efflux, the opening of a non-selective Na+/K+ channel, such as the 5-HT3 receptor leads to a dramatic influx of Na+, leading to depolarization and excitation.
Serotonin has been implicated in the etiology of many disease states, including depression, panic disorders, obsessive compulsive disorder, cardiac abnormalities, sleep disorders, eating disorders, nausea and vomiting, gastrointestinal cramps, and migraines. G-protein-coupled serotonin receptors have been implicated in the control of mood (5-HT1A), migraine (5-HT1B), pain perception (5-HT1D), smooth muscle contraction (5-HT2A, 5-HT7), anxiety (5-HT2C), and nausea (5-HT4). Activation of the 5-HT3 receptor by serotonin can either stimulate or inhibit cardiac function, induce vasodilation, affect lung and intestinal function, cause pain and sensitization of nociceptive neurons, and induce nausea and vomiting. Not surprisingly, many treatments for these disorders are thought to act through serotonergic pathways.
Several classes of drugs thought to modulate the serotonergic pathway exist. For example, selective serotonin re-uptake inhibitors (SSRIs) are used to treat depression. These antidepressants, including Prozac, Zoloft, and Paxil, are believed to act by potentiating serotonin levels at the synapse. Drugs, such as Imitrex, used to treat migraine headaches, act as selective serotonin receptor agonists. Other groups of drugs used to affect mood include monoamine oxidase inhibitors, and selective serotonin receptor antagonists.
While these drugs are administered to humans to treat the above-described disease states, the patients often unpredictably experience a number of side-effects including insomnia, anxiety, chest pain, hypertension, nausea, anorexia, sweating, chills, vomiting, diarrhea, constipation, decreased libido, and abnormal ejaculation. It has been hypothesized that the side-effects result from multiple receptor activation or inactivation when a serotonin agonist or antagonist is given as a treatment. Some of these improperly activated or inactivated receptors may lead to fast- or slow-acting excitatory responses, or slow-acting inhibitory responses, when really only one specific type of response is desired.
A better understanding of serotonin-associated cellular communication could greatly facilitate the discovery of drugs and therapeutic methodologies to treat a broad range of conditions with fewer of the serious and variable side-effects prevalent with currently available drugs that interface with the serotonin pathway. Exactly how the currently available drugs that interface with the serotonin pathway work is not well understood. Agonists, antagonists, and especially serotonin re-uptake inhibitors could affect numerous serotonin receptor subtypes, and the final outcome may be a combined readout of all these varied, and sometimes antagonistic, pathways. It has been hypothesized that the various undesirable side-effects of a given drug's action are the result of unwanted activation of the serotonin pathways that are not specific to the condition being treated. Therefore, compounds with a greater specificity for a specific serotonin receptor, for a limited subset of serotonin receptors, or for a specific subtype of a particular class of serotonin receptors would be invaluable to the field of therapeutics for serotonin-mediated disease states.